tbuckley/cabot-search huggingface dataset:
Abstract 6362: Overcoming resistance to immunotherapy due to loss of antigen presentation
Authors: Brian C. Miller, Yacine Choutri, Rose Al Abosy, Amy Huang, Emily K. Cox, Matthew P. Zimmerman, Wan Lin Chong, Katherine J. Vietor, Jenna Collier, Sarah A. Weiss, Debattama Sen, W. Nicholas Haining, Arlene H. Sharpe
Journal: Cancer Research (2023)

Abstract Resistance to immune checkpoint inhibitors represents a major therapeutic challenge, as only 40% of patients with melanoma (and less with other tumor types) have a long-term response to anti-PD-1 therapy. Resistance can arise because of somatic mutations in cancer cells that allow evasion of T cell-mediated killing. One commonly acquired resistance mutation in melanoma, loss of beta-2 microglobulin (B2m), prevents T cell killing by hiding cancer cells from CD8+ T cell recognition. To understand the failed immune response against resistant tumors, we used single-cell RNA-seq to characterize tumor-infiltrating immune cells in antigen presentation-deficient human melanoma biopsies and CRISPR-modified mouse melanoma tumors. Our data demonstrate an increase in immunosuppressive M2-like macrophages and absence of CD8+ T cells in B2m-null tumors. To overcome this resistance, we treated tumor-bearing mice with CD40 agonist antibody, which promotes differentiation of macrophages towards a pro-inflammatory phenotype and increases dendritic cell priming of CD8+ T cells. Treatment with CD40 agonist reduced tumor growth and improved tumor clearance in B2m-null melanoma and colorectal cancer models. To determine how CD40 agonist treatment works, we depleted different immune populations from the tumor microenvironment. We hypothesized that by depleting M2 macrophages, CD40 agonist treatment would remove an immunosuppressive brake to allow natural killer (NK) cells to kill tumor cells lacking MHC expression. To our surprise, NK cells were not required for the efficacy of CD40 agonist. Instead CD8+ T cells were required, even though the CD8+ T cells cannot directly recognize the tumor cells. scRNA-seq identified a transcriptionally unique state of CD8+ T cells that is recruited to the tumor microenvironment after CD40 agonist treatment. These CD8+ T cells produce IFNγ, which is required for the efficacy of CD40 agonist treatment. These data demonstrate that CD8+ T cells, a key mediator of anti-tumor immunity, can still be recruited to control tumors deficient in antigen presentation. More broadly, they suggest that strategies to activate CD8+ T cells may be effective even in the context of acquired resistance to checkpoint inhibitor therapy. Citation Format: Brian C. Miller, Yacine Choutri, Rose Al Abosy, Amy Huang, Emily K. Cox, Matthew P. Zimmerman, Wan Lin Chong, Katherine J. Vietor, Jenna Collier, Sarah A. Weiss, Debattama Sen, W. Nicholas Haining, Arlene H. Sharpe. Overcoming resistance to immunotherapy due to loss of antigen presentation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6362.
Abstract 6346: Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy
Authors: Hang Ke, Faming Zhang, Jialin Li, Feiyu Peng, Cen Chen, Henry Qixiang Li
Journal: Cancer Research (2023)

Abstract OX40, tumor necrosis factor receptor superfamily member 4, is an immune co-stimulatory receptor, together with its ligand OX40L, forming OX40-OX40L trimer-trimer complex between the surface of T-cells (OX40) and APCs/NKs (OX40L). OX40 expresses constitutively on Treg as well as on conventional Teff, particularly within TME. OX40/OX40L interactions directly triggers conventional T cell activation via NF-kB1 pathway and inhibits bcl-x and survivin to prevent apoptosis; and it also downregulates FoxP3/CTLA4, thus Treg function. OX40 agonistic antibodies have also been shown to activate tumor immunity and increase anti-tumor activity in preclinical models. Here we report that we identified/constructed a novel OX40-agonistic humanized IgG1 monoclonal antibody (mAb), HX011, with high affinity through hybridoma technology. HX011 was subsequently confirmed of the similar binding properties and functions as the original mouse mAb clone, 9C12: 1) binding to human OX40 (EC50 ~0.012 nM; 2) similar function binding in the reporter assay (EC50 ~6.6 nM); but 3) has little blockade of the OX40L binding to OX40. In another word, HX011 is similar to BMS-986178 for the first two assays, but contrastingly different for the third assay. Non-competing with OX40L may actually maximize T-cell activation, a potential advantage over a competing antibody. In vivo pharmacology modeling of HX011 in the humanized syngeneic CRC model, MC38, where syngeneic C57BL/6 mouse mice were knocked in with huOX40 (“HuGEMM-OX40”), demonstrated strong anti-tumor activity (TGI ~100% at 1 mg/kg, twice weekly). HX011 is being further investigated as a potential new immunotherapy for the treatment of cancers. Citation Format: Hang Ke, Faming Zhang, Jialin Li, Feiyu Peng, Cen Chen, Henry Qixiang Li. Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6346.
Abstract 5456: Application of a multiplex urinalysis test for predicting treatment response in patients with BCG unresponsive bladder cancer: a pilot study
Authors: Hideki Furuya, Kaoru Murakami, Ian Pagano, Runpu Chen, Yijun Sun, Nari Kim, Edward E. Kadel, Cheryl V. Wong, Nicole Davarpanah, Charles J. Rosser
Journal: Cancer Research (2023)

Abstract Introduction and Objective: Recently, we reported that OncuriaTM, a multiplex urinalysis test, could be predictive of BCG treatment response. Furthermore, high-grade BCG unresponsive bladder cancer have limited treatment options. Such patients are offered either radical cystectomy or systemic therapy. One of the systemic therapies include immune-oncology agents, e.g., PD-1 or PD-L1 inhibitors. In this study, we tested the performance of OncuriaTM in a BCG unresponsive cohort to determine if it could predict response to a PDL1 inhibitor. Methods: OncuriaTM data was evaluated in voided urine samples obtained from a prospectively collected cohort of 18 subjects who have BCG-unresponsive NMIBC with treatment of atezolizumab monotherapy or atezolizumab BCG combination (provided by Genentech, NCT02792192). The urine samples were collected prior to treatment in both arms. The OncuriaTM test, which measures 10 cancer-associated biomarkers was performed in an independent clinical laboratory. Predictive models were previously developed using supervised learning and cross-validation analyses. Model performance was validated using ROC curves. Results: Pre-treatment urinary concentrations of MMP9, VEGFA, CA9, SDC1, PAI1, APOE, A1AT, ANG and MMP10 were increased in patients who developed disease recurrence. A combinatorial predictive model of treatment outcome achieved sensitivity and specificity of &amp;gt;90%. Conclusion: Previous pilot study found that monitoring the urinary levels of a cancer-associated biomarker panel enabled the discrimination of patients who did not respond to intravesical BCG therapy. In this study, we noted the performance of OncuriaTM for the prediction of systemic PDL1 inhibitor treatment response. A limitation of this study includes its small sample size. With further study, the multiplex OncuriaTM test may be applicable for the clinical evaluation of bladder cancer patients who have not previously responded to intravesical BCG treatment and is considering systemic immune-oncology options. Citation Format: Hideki Furuya, Kaoru Murakami, Ian Pagano, Runpu Chen, Yijun Sun, Nari Kim, Edward E. Kadel, Cheryl V. Wong, Nicole Davarpanah, Charles J. Rosser. Application of a multiplex urinalysis test for predicting treatment response in patients with BCG unresponsive bladder cancer: a pilot study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5456.
Abstract 3857: Exploring mechanisms of resistance to elraglusib in pancreatic cancer PDX models
Authors: Taylor Weiskittel, Ding Li, Lingling Han, Joseph McDermott, Benedito Caneiro, Hu Li, Daniel Billadeau, Andrew Mazar
Journal: Cancer Research (2023)

Abstract Metastatic pancreatic cancer patients who previously progressed on nab-paclitaxel/gemcitabine (average of 3 previous lines if treatment) were treated with elraglusib in combination with a rechallenge of this combination. The majority of patients demonstrated a prolonged progression free survival. While this early clinical evidence is highly encouraging, the biological determinants of elraglusib response are unknown. In vitro screens of elraglusib on pancreatic PDX cell lines showed that some tumor cells possess modest intrinsic resistance to elraglusib as measured by LD50 which ranged from 316.9 nM to 1080 nM in a screen of 10 cell lines. To explore this phenomena further, we induced resistance in three cell line models by growing cells in the presence of increasing concentrations of elraglusib. We then sequenced the transcriptome of the parental and resistant lines to identify potential mechanisms of elraglusib resistance. Comparison of RNA sequencing profiles identified upregulation of the Aldo-keto reductase (AKR) family of genes. This upregulation was confirmed by qRT-PCR and by immunoblot demonstrating that AKRs were upregulated at both the transcriptomic and protein level. We further quantified the AKR levels in the remainder of the 10 cell lines and found that many of the more resistant lines had high expression of AKR1C2. However, not all of the resistant lines had high expression which could be because they have a separate mechanism of resistance to elraglusib. A large body of literature has found that AKR genes provide resistance to many other small molecule inhibitors either by direct metabolism or by indirectly relieving oxidative stress. Given these results, we identify aldo-keto reductases as potentially associated with elraglusib resistance, but further investigation is warranted to establish a causal link between AKR and the resistant phenotype. Citation Format: Taylor Weiskittel, Ding Li, Lingling Han, Joseph McDermott, Benedito Caneiro, Hu Li, Daniel Billadeau, Andrew Mazar. Exploring mechanisms of resistance to elraglusib in pancreatic cancer PDX models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3857.
Abstract 380: BaF3-BTK engineering cell lines as a useful platform for novel BTK inhibitor discovery
Authors: Guoqian Wang, Hongling Chen, Yu Wang, Jingxiao Xu, Lin Zhou, Yao Tang, Jinying Ning, Feng Hao
Journal: Cancer Research (2023)

Abstract Introduction: Bruton's tyrosine Kinase (Btk) plays an essential role in BCR signaling and has been a hot new target in molecular targeted therapy in the past few years, led by the clinical success of ibrutinib and acalabrutinib, two first approved BTK inhibitors, that greatly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Currently, there are 5 approved BTK inhibitors including additionally zanubrutinib, orelabrutinib and velexbru. Up to 24 BTK inhibitors are under active clinical evaluation as antineoplastic drugs against chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B-cell malignancies and mantle cell lymphoma (MCL) in different countries. However, the acquired resistance due to the C481S mutation in BTK remains an essential challenge to improve the poor prognosis of the patient. Subsequently, several next-generation BTK inhibitors are under clinical evaluation targeting the BTK-C481S mutation, such as LOXO-305, a highly selective and non-covalent BTK inhibitor which potently inhibits the cellular activity of BTK C481S/T/R mutations. Methods: Our group has generated 9 Ba/F3-BTK engineering cell lines as useful cell line and xenograft models for novel BTK inhibitor discovery and development. They harbor wild type BTK or ibrutinib resistance BTK mutations such as the C481S and C481S-double mutations, and the T474M/I mutations. Moreover, we generated Ba/F3-ETV6-BTK-F517L and Ba/F3-ETV6-BTK-C481S-F517L cell lines using a dose-escalation method after treating cells with a mutagenic agent. The BTK-F517L mutation is highly resistant to both ibrutinib and LOXO-305 treatment. Crystal structure analysis and 3D modeling revealed that the F517L mutation may affect the conformation of the BTK binding pocket to ibrutinib, indicating novel BTK inhibitors may be needed to overcome this resistance mutation. Conclusion: The Ba/F3-BTK engineering cell lines can be a useful tool to develop and evaluate next-generation BTK inhibitors and to explore new acquired resistance BTK mutations. Citation Format: Guoqian Wang, Hongling Chen, Yu Wang, Jingxiao Xu, Lin Zhou, Yao Tang, Jinying Ning, Feng Hao. BaF3-BTK engineering cell lines as a useful platform for novel BTK inhibitor discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 380.
Abstract 5395: Improving survival prediction using flexible late fusion machine learning framework for multi-omics data integration
Authors: Nikos Nikolaou, Domingo Salazar, Harish RaviPrakash, Miguel Goncalves, Gustavo Alonso Arango Argoty, Nikolay Burlutsky, Natasha Markuzon, Etai Jacob
Journal: Cancer Research (2023)

Abstract Improving cancer patients Overall Survival (OS) prognosis is critical for personalization of treatment using model-identified drivers of cancer progression. Current cancer prognosis models largely rely on clinical and demographic patient characteristics. Adding ‘omics’-based modalities can help improve patient OS prediction and lead to better disease categorization and understanding. We introduce a data driven methodology for combining multi-omics and clinical data, including clinical/demographics, mutations, gene expression, long non-coding and micro-RNA expression, DNA methylation, and proteomics for improving prediction of OS in cancer patients. High dimensionality of ‘omics’ modalities present challenges to combining them into one model. We propose a late stage modalities fusion where we construct a separate data driven model for OS prediction for each modality, later combining individual predictions in a final linear OS prediction model. With a limited number of patients to develop the model, such an approach helps to better protect against overfitting, and allows to account for different degrees of informativeness of modalities by weighting them according to individual success. We introduce a robust machine learning pipeline with rigorous training, testing and evaluation capabilities, and demonstrate its effectiveness on a suit of TCGA data. When comparing early vs. late fusion of omics and clinical modalities for survival prediction using NSCLC TCGA data, we observe the C-index improvement from 0.57±.04 to 0.61±.01. Best individual modality performance was at 0.59±.02 using clinical modality. Dominant modalities in unimodal survival analysis varied between cancers, with clinical, RNA, and miRNA for LUAD, and clinical, RNA, and RPPA for LUSC. Using pan-cancer TCGA data for survival prediction, the best C-index = 0.77 was achieved using multi-omics model, followed by 0.76±.01 for clinical, 0.75±.01 for RNA seq, and 0.73±.01 for RPPA unimodal models. Citation Format: Nikos Nikolaou, Domingo Salazar, Harish RaviPrakash, Miguel Goncalves, Gustavo Alonso Arango Argoty, Nikolay Burlutsky, Natasha Markuzon, Etai Jacob. Improving survival prediction using flexible late fusion machine learning framework for multi-omics data integration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5395.
Abstract 4745: Prostatic fluid-based cfDNA methylation profiling distinguish benign hyperplasia from prostate cancer
Authors: Hang Dong, Haoran Tang, Yue Zhang, Shidong Jia
Journal: Cancer Research (2023)

Abstract Introduction: A challenge in the early diagnosis of prostate cancer (PC) is to distinguish between malignant tumor and benign prostatic hyperplasia (BPH) because of the similar symptoms. Methylation profiles provide a way for discriminating BPH from PC, which could prevent overdiagnosis and overtreatment. Applying methylation biomarkers to liquid biopsy specimens provides higher sensitivity to detect tumors. Methods: Prostatic fluid samples were prospectively collected from 40 patients following digital rectal exam and isolated cell-free DNA to perform whole genome methylation sequencing using PredicineEPIC platform. Combing differentially methylated regions (DMR) with methylation signature identified from massive public data, a panel of methylation patterns was developed. The difference of methylation signal in profiled region were implemented by machine learning to robustly distinguish BPH from prostate cancer. Results: We identified 324 biomarkers from prostatic fluid samples and collected 46 methylation biomarkers reported from previous research. Regions with extreme difference between benign prostatic hyperplasia and prostate cancer were identified as candidate biomarkers. A diagnostic model trained on these 55 biomarkers could distinguish BPH from PC in 10-fold cross-validation (AUC = 0.92). And this model could be applied for discriminating normal tissue from prostate tumor tissue with highly performance (AUC &amp;gt; 0.95). Using this set of regions, we developed an NGS-based panel for detecting methylation alteration of cfDNA from prostate liquid, which inherited the ability of differentiation. Conclusion: These methylation patterns could be developed as the novel biomarkers to support the development of prostatic fluid-based non-invasive diagnostic test and reduce unnecessary biopsies. This panel could be applied for differential diagnosis of benign hyperplasia and prostate cancer. Citation Format: Hang Dong, Haoran Tang, Yue Zhang, Shidong Jia. Prostatic fluid-based cfDNA methylation profiling distinguish benign hyperplasia from prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4745.
Abstract 2105: Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer
Authors: Shawn Malone, Christopher Wallis, Scott Morgan, Amar Kishan, Amy Tu Trinh Le, Julia Malone, Yilun Sun, Daniel Spratt, Fred Saad, Soumyajit Roy
Journal: Cancer Research (2023)

Abstract Background: Studies on metastatic hormone sensitive prostate cancer have shown that metachronous presentation has a better prognosis compared to synchronous disease. However, it remains unknown if such association is pertinent in metastatic castrate resistant prostate cancer (mCRPC). We performed a secondary analysis of ACIS study to determine if the response to dual androgen receptor axis-targeted therapy (ARAT) in in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC) varies based on M-stage at diagnosis and if prior local therapy plays an effect modifying role in the association of M-stage at presentation with survival. Patients and Methods: In this phase III randomized controlled trial, mCRPC patients with no prior exposure to androgen biosynthesis signaling inhibitors were randomly assigned to either apalutamide or placebo combined with abiraterone and prednisone. Cox regression models were applied for radiographic progression-free survival (rPFS), overall survival (OS) with interaction terms between M-stage and treatment regimen. Multivariable Cox regression analyses were performed to determine the adjusted association of M-stage with rPFS and OS after considering the effect modification by prior local therapy (LT). Results: Among 972 evaluable patients -432 had M0, 334 had M1 at diagnosis while M-stage was unknown in 206. We did not find any statistically significant heterogeneity of treatment effect on rPFS (interaction p=0.13; HR for placebo in M0 group: 1.42 [1.13-1.79]; M1/unknown group: 1.11 [0.90-1.37]), and OS (interaction p=0.87; HR for placebo in M0 group: 1.02 [0.81-1.29], and M1/unknown group: 1.00 [0.82-1.23]) based on M-stage at diagnosis. There was no significant association of M-stage with rPFS (HR for LT group: 1.08 [0.84-1.40], HR for no LT: 0.91 [0.67-1.24]) and OS (HR for LT: 1.04 [0.81-1.33] and no LT: 0.95 [0.70-1.29]) with no significant heterogeneity depending on receipt of LT (interaction p-value of 0.94 and 0.93, respectively). Conclusion: We did not find a statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation. M-stage was not found to be a predictor for rPFS and OS after considering effect modification by prior LT. Citation Format: Shawn Malone, Christopher Wallis, Scott Morgan, Amar Kishan, Amy Tu Trinh Le, Julia Malone, Yilun Sun, Daniel Spratt, Fred Saad, Soumyajit Roy. Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2105.